In an effort to understand and to overcome the factors that thwart replication of genetic association studies, we recently studied variants in the conserved regions of the gene (IDE) that encodes the insulin/AB degrading enzyme gene in considerable detail. A remarkably high percentage of these variants had modest effects that showed replicable association when analyzed in our large case/control series. Based on these results, our current working hypothesis is that progress in identifying novel LOAD genes has been slow because most LOAD genes are like IDE; they have multiple susceptibility alleles with modest effect size. The effect of genes with powerful variants like the ApoE 4 allele is easily detected and replicated in small case/control series. But the net effect of genes with multiple susceptibility alleles that have modest effects, though substantial, cannot be detected and replicated well unless large case/control series are employed to evaluate a set of variants selected for their likely functional effect. Using the scientific infrastructure developed in the last cycle we propose to pursue this hypothesis by targeting genes in the AB processing pathway. We will perform an unbiased, genome-wide search for AB QTLs likely to harbor novel LOAD genes in the AB processing pathway. In addition, we will search thoroughly for and examine the function of additional susceptibility alleles in the known, major genes of the AB processing pathway. Our specific aims are to (1) perform whole genome scans to identify novel quantitative trait loci (QTLs) linked to plasma AB levels, (2) identify novel LOAD susceptibility alleles by using multiple, large case control series to analyze the variants in conserved regions of major genes in the AB processing pathway (SORL1, APP, IDE, MME, ECE1, PLAU, BACE1, PSEN1, PSEN2, and VR22), and (3) evaluate the functional effects of the susceptibility alleles identified in specific aim 2. Depending on the specific location of each susceptibility allele identified, function will be analyzed by evaluating the effect of the variant on (i) plasma AB and/or (ii) brain mRNA. Our recent results suggest that many susceptibility alleles may act by altering gene expression or splicing. There is strong evidence that reducing the AB42 peptide in normal elderly subjects could prevent Alzheimer's disease (AD), a disorder that inflicts enormous suffering and financial loss on our society. To perform affordable prevention trials and administer drugs to normal elderly people with an acceptable risk/benefit ratio, methods must be developed for identifying those elderly individuals who are at increased risk for AD. In this application, we propose experimentation to identify many genes with variants that alter AB42 thereby influencing risk for AD; we do so because each new AD gene identified opens new therapeutic possibilities and improves our ability to identify the at risk population.